Nickel-catalyzed coupling of aryl iodides with aromatic aldehydes: Chemoselective synthesis of ketones

Article abstract of DOI:10.1021/jo010289i

Aryl iodide (ArI) couple with aryl aldehydes (Ar'CHO) in the presence of Ni(dppe)Br₂ and Zn to give the corresponding biaryl ketones (ArCOAr′). The use of a bidentate phosphine complex is critical to the success of this catalytic reaction. The

Full text of DOI:10.1021/jo010289i

1682
J . Org. Chem. 2002, 67, 1682-1684
iodides with N-pyrazyl aldimines to form the correspond-
ing ketimines, which form ketones upon hydrolysis, was
reported by Hartwig et al.6c The formation of ketones by
this method requires two reaction steps and very high
temperature.
Our ongoing interest in nickel-mediated carbon-
carbon bond forming reactions7 led us to explore the
reactions of aryl halides with aldehydes. In this paper,
we wish to report for the first time a nickel-catalyzed
coupling of aryl iodides with aldehydes to give ketones
in fair to good yields (eq 1). This convenient one-pot
synthesis of ketones appears to involve both addition of
aryl group to aldehydes and â-hydride elimination of the
resulted alkoxide in the same reaction system.
Nick el-Ca ta lyzed Cou p lin g of Ar yl Iod id es
w ith Ar om a tic Ald eh yd es: Ch em oselective
Syn th esis of Keton es
Yi-Chun Huang, Kanak Kanti Majumdar, and
Chien-Hong Cheng*
Department of Chemistry, Tsing Hua University, Hsinchu,
Taiwan 300
chcheng@mx.nthu.edu.tw
Received March 15, 2001
Abstr a ct: Aryl iodides (ArI) couple with aryl aldehydes
(Ar′CHO) in the presence of Ni(dppe)Br2 and Zn to give the
corresponding biaryl ketones (ArCOAr′). The use of a bi-
dentate phosphine complex is critical to the success of this
catalytic reaction. The reaction provides a new procedure
for the synthesis of various functionalized biaryl ketones.
The methods available for direct synthesis of ketones
from alkyl or aryl halides are few and usually require a
multistep process in classical organic synthesis. Most of
these reactions involve the oxidation of the corresponding
secondary alcohols using more than stoichiometric amount
of chromium reagents as the oxidizing agent.1 Aromatic
ketones can be synthesized from Friedel-Crafts reaction
via acylation in the presence of AlCl3. This method
provides ketones directly from aromatic hydrocarbons
and has been known for many years.2 The coupling of
organometallic reagents with acyl chlorides using transi-
tion metals as catalysts usually provides ketones in high
yields,3,4 but anhydrous conditions should be maintained
for both the reaction partners. Miyaura, Suzuki and co-
workers reported a palladium-catalyzed synthesis of
benzophenones or benzyl ketones via the cross-coupling
of arylboronic acids with aryl halides, triflates, or benzyl
halides under carbon monoxide atmosphere.5 Reports for
direct ketone synthesis from organic halide and alde-
hydes via activation of aldehyde hydrogen by transition
metal catalysts are also available.6a-b However, these
reactions are limited with respect to substrates and/or
require more than stoichiometric amount of metal salts.
Very recently, a rhodium(I)-catalyzed coupling of aryl
Treatment of iodobenzene (1a ) with benzaldehyde (2a )
in the presence of Ni(dppe)Br2 (10%) and Zn at 110 °C
under N2 in THF gave benzophenone (3a ) in 84% yield.
Under similar reaction conditions, bromobenzene af-
forded only a small amount of ketone 3a (23%), the major
product being diphenylcarbinol (67%). As our previous
findings,8 the catalytic reaction proceeds smoothly only
with bidentate phosphine nickel complexes. Monodentate
phosphine complexes are completely ineffective, whereas
Ni(dppm)Br2, Ni(dppe)Br2, Ni(dppp)Br2, and Ni(dppb)-
Br2 afforded 3a in 74, 84, 77, and 32% yields, respectively.
Under similar conditions, palladium complexes Pd-
(dppe)2X2 (X ) Cl and Br) gave no expected product at
all. Solvent plays a crucial role in this catalytic reaction.
THF is superior to other solvents. In low polarity solvent
such as toluene the catalytic reaction did not occur at
all. In acetonitrile or DMF several unknown side products
along with benzyl alcohol, the reduction product of
benzaldehyde, was observed. At refluxing temperature
of THF the reaction gave a mixture of benzophenone and
(1) (a) Hudlicky, M. In Oxidations in Organic Chemistry; ACS
Monograph 186; American Chemical Society: Washington, DC, 1990.
(b) Larock, R. C. In Comprehensive Organic Transformations; VCH:
New York, 1989; p 591.
(2) (a) Olah, G. In Friedel-Crafts and Related Reactions; Inter-
science Publishers: New York, 1964; Vol. III, p 1259. (b) Osman, M.
Helv. Chim. Acta 1982, 65, 2448. (c) Zimmerman, H. E.; Paskovich,
D. H. J . Am. Chem. Soc. 1964, 86, 2149. (d) Heitzler, F. R.; Hopf, H.;
J ones, P. G.; Bubenitschek, P.; Lehne, V. J . Org. Chem. 1993, 58, 2781.
(3) (a) Cardellicchio, C.; Fiandanese, V.; Marchese, G.; Ronzini, L.
Tetrahedron Lett. 1987, 28, 2053. (b) Malanga, C.; Aronica, L. A.;
Lardicci, L. Tetrahedron Lett. 1995, 36, 9185.
(4) (a) Haddach, M.; MaCarthy, J . R. Tetrahedron Lett. 1999, 40,
3109. (b) Bumagin, N. A.; Korolev, D. N. Tetrahedron Lett. 1999, 40,
3057. (c) Kabalka, G. W.; Malladi, R. R.; Tejedor, D.; Kelley, S.
Tetrahedron Lett. 2000, 41, 999 and references therein.
(5) (a) Ishiyama, T.; Kizaki, H.; Hayashi, T.; Suzuki, A.; Miyaura,
N. J . Org. Chem. 1998, 63, 4726. (b) Ishiyama, T.; Kizaki, H.; Miyaura,
N.; Suzuki, A. Tetrahedron Lett. 1993, 34, 7595.
(7) (a) Kong, K.-C.; Cheng, C.-H. J . Chem. Soc., Chem. Commun.
1991, 423. (b) Kong, K.-C.; Cheng, C.-H. Organometallics 1992, 11,
1972. (c) Feng, C.-C.; Nandi, M.; Sambaiah, T.; Cheng, C.-H. J . Org.
Chem. 1999, 64, 3538. (d) Sambaiah, T.; Li, L. P.; Huang D. J .; Lin, C.
H.; Rayabarapu, D. K.; Cheng, C.-H. J . Org. Chem. 1999, 64, 3663. (e)
Sambaiah, T.; Huang, D. J .; Cheng, C.-H. J . Chem. Soc., Perkin Trans.
1 2000, 195.
(6) (a) Hirao, T.; Misu, D.; Agawa, T. J . Am. Chem. Soc. 1985, 107,
7179. (b) Satoh, T.; Itaya, T.; Miura, M.; Nomura, M. Chem. Lett. 1996,
823. (c) Ishiyama, T.; Hartwig, J . J . Am. Chem. Soc. 2000, 122, 12043.
(8) Majumdar, K. K.; Cheng, C.-H. Org. Lett. 2000, 2, 2295.
10.1021/jo010289i CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/08/2002

Notes
J . Org. Chem., Vol. 67, No. 5, 2002 1683
Ta ble 1. Syn th esis of Bia r yl Keton es in th e P r esen ce of
Ni(d p p e)Br 2/Zn a
tones in fair to good yields. However, aryl iodides with
electron-withdrawing groups need longer reaction time,
and the product yields are comparatively lower. This may
be attributed to lower nucleophilicity of these aryl groups.
The arylation of aliphatic aldehydes such as n-butyral-
dehyde and n-hexaldehyde was slower, and the corre-
sponding yields are low probably because of the poorer
electrophilicity of aliphatic aldehydes compared to aro-
matic aldehydes (entries 7, 9). The position of a substitu-
ent on aryl iodides also influences the yield of the
reaciton. Ortho-substituted aryl iodides usually give
lower yields than do meta- or para-substituted ones
(entries 10-12).
As illustrated in Table 1, this methodology chemose-
lectively transforms a variety of aryl iodides and alde-
hydes into the corresponding ketones in the presence of
functional groups that readily react with organolithiums
or Grignard reagents (entries 3-5, 14, 15). Heterocyclic
ketones can also be easily prepared by our method.
Iodobenzene reacted smoothly with 2-thiophenecaboxal-
dehyde under similar reaction conditions to give phenyl-
(2-thienyl)methanone (3f). Product 3f can also be pre-
pared alternatively by treating 2-iodothiophene with
benzaldehyde (entry 13). In most of these reactions, small
amounts of biaryls (3-11%) and pinacols (2-5%) were
detected. For biaryl formation, electron-donating aryl
iodides are slightly more favorable than electron-with-
drawing ones. Biaryl formation is due to the homocou-
pling of aryl iodides 9 and pinacol formation is caused by
the presence of ZnI2 formed in situ in the reaction
mixture.10
Based on the established nickel chemistry and forego-
ing results, we proposed the following mechanistic path-
ways (Scheme 1) to account for the present catalytic
process. Reduction of Ni(II) to Ni(0) by zinc metal with
the formation of zinc halide likely initiates the catalytic
reaction. Oxidative addition of aryl iodides to Ni(0)
generates organonickel(II) species 4. Zinc halide (a Lewis
acid) abstraction of an iodide from 4 forms a cationic
nickel species 5. Coordination of aldehyde affords a nickel
intermediate with the aryl group cis to the coordinated
aldehyde because of the bidentate chelating phosphine
ligand. Migration of the aryl group to the carbonyl carbon
of coordinated aldehyde affords a nickel alkoxide 6.
Subsequent â-hydride elimination gives the desired
ketone and nickel hydride 7. Reaction of HX generated
from reductive elimination of 7 with Zn powder affords
zinc halide with evolution of H2.11
The formation of Ni(0) in the first step gains support
from the fact that when Ni(dppe)Cl2, Ni(dppe)Br2 or Ni-
(dppe)I2 is used, the presence of zinc powder is necessary
to initiate the reaction. The proposed iodide dissociation
is evidenced by the observation that a stoichiometric
reaction of iodobenzene (1a ) with benzaldehyde (2a ) in
a
Reaction conditions: aryl iodide (1.25 mmol), aldehyde (1.00
mmol), Ni(dppe)Br2 (0.100 mmol), Zn (2.75 mmol) in THF (4 mL)
at 110 °C. Satisfactory spectra of 1H, 13C NMR, and MS for each
b
product were obtained. c Isolated yields; yields were based on
d
aldehyde used. Iodobenzene (1.00 mmol), aldehyde (1.50 mmol)
were used and yields were based on iodobenzene.
(9) (a) Semmelhack, M. F.; Helquist, P.; J ones, L. D.; Keller, L.;
Mendelson, L.; Ryono, L. S.; Smith, J . G.; Stauffer, R. D. J . Am. Chem.
Soc. 1981, 103, 6460. (b)Yamamoto, T.; Wakabayashi, S.; Osakada,
K. J . Organomet. Chem. 1992, 428, 223.
(10) Tanaka, K.; Kishigami, S.; Toda, F. J . Org. Chem. 1990, 55,
2981.
(11) Detection of H2: To a sidearm flask were added Ni(dppe)Br2
(0.10 mmol), Zn (2.75 mmol), iodobenzene (1.25 mmol), benzaldehyde
(1.00 mmol), and THF (4.0 mL). The flask was flashed several times
with N2, and the N2 gas was then partially evacuated. The sealed
reaction flask was heated at 65 °C for 4 h. The flask was cooled to
room temperature, and the inside gas was sampled by a pressure-lock
syringe and was analyzed by a mass spectrometer (Finnigan MAT 95
XL). A sharp peak at mass number 2.0 confirms the presence of H2.
diphenylcarbinol in a 73/27 ratio. However, at higher
temperature (110 °C), benzophenone (3a ) was formed
exclusively.
This nickel-catalyzed ketone formation was success-
fully extended to a series of aldehydes and aryl iodides.
The results of these studies are listed in Table 1. Most
aryl iodides bearing either electron-rich or electron-
withdrawing substituents reacted smoothly to give ke-

1684 J . Org. Chem., Vol. 67, No. 5, 2002
Notes
Sch em e 1
sealed with the screw cap quickly under N2. The system was
heated at 110 °C with stirring for 30 h. The reaction mixture
was cooled to room temperature, diluted with ether, filtered
through a thin Celite pad, and washed with ether. The filtrate
was concentrated, and the crude residue was purified through
a silica gel column using hexane/EtOAc (V/V ) 95/5) as eluent
to give 3c (0.119 g) in 57% yield. 1H NMR (CDCl3) δ 7.48 (t, 2
H, J ) 7.8 Hz), 7.61 (t, 1 H, J ) 7.8 Hz), 7.75 (d, 2 H, J ) 7.7
Hz), 7.76 (d, 2 H, J ) 7.7 Hz), 7.84 (d, 2 H, J ) 7.6 Hz); 13C
NMR δ 115.53, 117.93, 128.54, 129.98, 130.15, 132.08, 133.24,
136.21, 141.11, 194.96; IR (neat) 2241, 1658 cm-1; HRMS calcd
for C14H9ON 207.0684, found 207.0680.
the presence of Ni(cod)2/dppe (1:1) did not give any
benzophenone (3a ). However, the same reaction proceeds
smoothly, giving 48% isolated yield of 3a in the presence
of 1 equiv of ZnI2. The result strongly indicates that zinc
halide abstracts an iodide from the nickel center and
creates a vacant coordination site for the aldehyde. It
should be noted here that although biaryl ketone was
formed, no H2 was detected. However, for the same
reaction in the presence of Zn and ZnI2, H2 gas was
evolved. Therefore, H2 was formed only after reaction
with Zn. For each ketone formed, the catalytic reaction
produces a HI (or the equivalent) based on the stoichi-
ometry (eq 1). It is likely that zinc metal acts as a proton
scavenger by converting the acid produced into H2 gas
in the reaction.
In conclusion, we have demonstrated a highly chemose-
lective nickel-catalyzed coupling reaction of aryl iodides
with aryl aldehydes to give the corresponding ketones
in good yields. The simple experimental operation makes
this catalytic reaction a convenient and straightforward
route for the synthesis of ketones, in particular, of
functionally substituted ketones. Attempt to extend the
scope of our new procedure to the synthesis of more
complex molecules is underway.
All other products were identified by comparison of 1H, 13C
NMR, IR, and mass spectra with those of the authentic samples
or the reported values. For references, the Chemical Abstracts
Service registry numbers of these products are listed below.
Dip h en ylm eth a n on e (3a ) [119-61-9]; (2,4-d im eth oxy-
p h en yl)(p h en yl)m eth a n on e (3b) [3555-84-8]; (4-ch lor o-
p h en yl)(p h en yl)m eth a n on e (3d ) [134-85-0]; (2,4-d ich lo-
r op h en yl)(p h en yl)m eth a n on e (3e) [19811-05-3]; p h en yl(2-
th ien yl)m eth a n on e (3f) [135-00-2]; 1-p h en yl-1-bu ta n on e
(3 g) [495-40-9]; d i(4-m eth oxyp h en yl)m eth a n on e (3h ) [90-
96-0]; 1-p h en yl-1-h exa n on e (3i) [942-92-7]; d i(4-m eth yl-
p h en yl)m eth a n on e (3j) [611-97-2]; (3-m eth ylp h en yl)(4-
m et h ylp h en yl)m et h a n on e (3k ) [13152-94-8]; (2-m et h yl-
p h en yl)(4-m eth ylp h en yl)m eth a n on e (3l) [1140-16-5]; 1-(4-
ben zoylp h en yl)eth a n on e (3m ) [53689-84-2]; eth yl-4-ben -
zoylben zoa te (3n ) [15165-27-2]; 1-n a p h th yl(p h en yl)m eth -
a n on e (3o) [642-29-5]; 9-p h en a n th r yl(p h en yl)m eth a n on e
(3p ) [6453-95-8].
Exp er im en ta l Section
Rep r esen ta tive P r oced u r e for th e Cou p lin g of Ar yl
Iod id es w ith Ald eh yd es. Ni(dppe)Br2 (0.062 g, 0.10 mmol) and
Zn powder (0.180 g, 2.75 mmol) were placed in a screw-capped
vial. The vial was flashed with N2 and then sealed with septum.
Iodobenzene (0.255 g, 1.25 mmol), 4-cyanobenzaldehyde (0.131
g, 1.00 mmol), and THF (4.0 mL) were added to the reaction
mixture via syringe. The septum was removed, and the vial was
Ack n ow led gm en t. Financial support from National
Science Council of the Republic of China is greatly
acknowledged. One of the authors, K.K.M., thanks NSC
for a postdoctoral research fellowship.
J O010289I